Cardiovascular Disease Prevention: A Look Ahead Jacques Genest MD

Transcription

1 Cardiovascular Disease Prevention: A Look Ahead Jacques Genest MD Cardiovascular Research Laboratories Research Institute of the McGill University Health Center

2 Disclosure J. Genest MD 2011 Advisory Board, Speaker s Bureau, Consultant, Grants AstraZeneca Merck * Pfizer Novartis AMGEN * Roche * Biotech: Danone; Acasti ; Nutrasource Stock ownership: none; Off label use: none * Scientific Advisory Relevant disclosure: JUPITER, IMPROVE-IT, CANTOS, REVEAL steering Committees.

3 Guidelines for the Diagnosis and Treatment of Dyslipidemia and Prevention of Cardiovascular Disease 2009 Text and Slides (Fr. & Engl) Available at:

4 Introduction: Burden of Disease CVD causes 1:3 deaths in Canada Neurodegenerative 2% Causes of Death, Canada Psychiatric 5% Diabetes 3% Other 17% Heart 34% Accidents 4% Cancer 27% Respiratory 8% StatsCan/Canada

5 Introduction: Burden of Disease CVD causes 1:3 deaths in Canada Neurodegenerative 2% Other Psychiatric 17% proportion of 5% deaths due to cardiovascular Accidents 4% Causes of Death, Canada In Canada, between 2000 and 2007, the Cancer 27% Heart 34% disease has Diabetes declined from 32.4% to 27.4%, while 3% that of cancers has remained stable (28.7% to 29.6%). Respiratory 8% StatsCan/Canada

6 Screening C Men over 40 and postmenopausal women Anyone with atherosclerosis regardless of age Anyone with diabetes regardless of age Family history of premature CVD (<60 yrs) Arterial hypertension (Check metabolic disorder, dyslipidemia) Inflammatory diseases (lupus, rheumatoid arthritis, psoriasis)

7 Screening C Children of patients with severe dyslipidemia HIV infection with HAART therapy Clinical hyperlipidemias (xanthomas, xanthelasmas, premature arcus corneus) Erectile dysfunction Chronic renal disease

8 Risk Assessment CV risk assessment remains imperfect Framingham Risk Score (CVD) [FRS may underestimate risk in some patients] Reynolds Risk Score (CVD) [RRS web-based, includes family history and hscrp] We now recommend Cardiovascular Risk (Total CVD) assessment, not only CAD. As CHEP and CDA do.

9 Recommended Lifestyle Changes: Smoking cessation Diet: fruit, vegetables, decreased saturated fats, decreased salt intake Calorie restriction for ideal body weight Daily exercise (30-60 min) Stress management

10 Target Levels Risk Level Initiate treatment if: High Consider treatment in all patients CAD,PVD Atherosclerosis Most Pts with Diabetes FRS 20% RRS 20% Moderate (strive towards ) FRS 10-19% LDL-C>3.5 mmol/l TC/HDL >5.0 hscrp >2 men 50+, women 60+ Family history and hscrp modulate risk Primary LDL-C <2 mmol/l Or 50% LDL-C Class A I Level A <2 mmol/l Or 50% LDL-C Class A IIA Level A Primary Alternate ApoB<0.80 A Class I Level A ApoB<0.80 Class A IIA Level A Low FRS<10% LDL-C>5.0mmol/L 50% LDL-C A

11 Residual Risk (When LDL-C at target) OPTIONAL Secondary Targets Test Cut-point Intervention TC/HDL-C >4.0 Niacin Fibrate Non HDL-C >3.5 mmol/l Niacin Fibrate Apo B/AI >0.8 Niacin Ezetimibe Triglycerides hscrp >1.7 mmol/l >2.0 mg/l Fibrate Niacin Statin Ezetimibe Genest J et al. Can J Cardiol 2009 Oct;[in press].

12 Biomarkers and Cardiovascular Risk: Update 2011 Circulation. 2010;122:e JACC 2010;50:

13 BIOMARKERS: Serum/Plasma Apolipoproteins* Atrial Natriuretic Peptide (ANP) hscrp HgA1c Lipoprotein-associated phospholipase A2 Inflammatory biomarkers (spla2, IL) Homocysteine Class III Class III Class IIa Class IIb Class IIb N/A N/A * Apo AI, apo B, LDL particle size by gel or NMR, HDL particle size, density JUPITER indications (Same as in Canada)

14 Imaging Resting ECG Stress ECG Myocardial perfusion imaging Coronary Calcium score Coronary computed tomography angiography Transthoracic echocardiogram Carotid Intima-Media Thickness Flow-mediated vasodilatation / Arterial Stiffness Ankle-Brachial Index (ABI) Magnetic Resonance imaging of plaques

15 Imaging (For risk stratification) Resting ECG Stress ECG MIBI Coronary Ca ++ score CT angiography TT echocardiogram Stress Echo Carotid IMT FMD/ Arterial Stiffness ABI MRI of plaques Class IIa Class IIb Class IIb Class IIa (FRS 10-19%) Class III Class IIb - III Class III Class IIa Class III Class IIa Class III

16 Take Home Point: Imaging Despite appeal of imaging techniques, little data exist on the effects of such strategies on outcomes C-IMT and Coronary Ca Score might be useful in the intermediate risk category

17 Recommendations 2010

18 Genome-Wide Scans for CAD and MI Samani NJ. NEJM 2007;357:443

19 2011 Published online 6 March 2011

20 Recommendations 2011

21 Conclusions

22 2009 Canadian Lipid Guidelines Update 2012 New Information since 2009 Involvement of CIHR (C-CHANGE) Meta-analysis (CTT, CVD, Cancer) Primary prevention Controversy Safety and Efficacy of low reaching LDL-C Role of biomarkers in determining risk Role of imaging in determining risk Definition of obesity SHARP trial Role of genetics in risk prediction

23 Risk Assessment and Treatment Targets Risk Assessment HIGH FRS 20% RRS 20% Moderate FRS 10-19% Initiate/consider treatment if any of the following: CAD PVD Atherosclerosis Most Diabetic Patients (consider treatment in all patients) LDL-C > 3.5 mmol/l TC/HDL-C > 5.0 hscrp > 2 mg/l * Family history (strive towards ) Primary Target LDL-C < 2 mmol/l or LDL-C 50% A LOW FRS < 10% LDL-C > 5.0mmol/L LDL-C 50% A Genest J et al. Can J Cardiol 2009 Oct;[in press].

24 Old drugs Niacin (AIM High, HPS2 Thrive) Fibrates (ACCORD Fenofibrate) Ezetimibe (SHARP Trial) Bile Acid Sequestrants (When you don t like your patient ) Extracorporeal LDL filtration techniques

25 On-Going Studies: Ezetimibe IMPROVE-IT: IMProved Reduction of Outcomes: Vytorin Efficacy International Trial Age: >18 years, ACS Simvastatin 40mg daily +/- ezetimibe 10mg Randomized to: Simvastatin 40 or Vytorin 40/10 n=18, Sponsor: Merck

26 The results of the Study of Heart and Renal Protection (SHARP) Colin Baigent, Martin Landray on behalf of the SHARP Investigators Disclosure: SHARP was sponsored, designed, run, and analysed by the University of Oxford. Funding was received from Merck, the UK MRC, British Heart Foundation, and Australian NHMRC.

27 Study of Heart and Renal Protection (SHARP) Largest study of lipid-lowering therapy in CKD patients 9,438 CKD patients without overt CVD 6,382 patients with stage 3-5 CKD not on dialysis 3,056 patients on dialysis Ezetimibe 10 mg/simvastatin 20 mg vs. placebo Am Heart J 2010; e10

28 SHARP: Main outcomes Key outcome Major atherosclerotic events (coronary death, MI, nonhaemorrhagic stroke, or any revascularization) Subsidiary outcomes Major vascular events (cardiac death, MI, any stroke, or any revascularization) Components of major atherosclerotic events Main renal outcome End stage renal disease (dialysis or transplant)

29 Proportion suffering event (%) SHARP: Major Atherosclerotic Events Risk ratio 0.83 ( ) Logrank 2P= Placebo Eze/simv Years of follow-up

30 Proportional reduction in atherosclerotic event rate (95% CI) CTT: Effects on Major Atherosclerotic Events 30% Statin vs control (21 trials) 25% 20% 15% 10% 5% More vs Less (5 trials) SHARP 0.82mmol/L SHARP 17% risk reduction 0% Mean LDL cholesterol difference between treatment groups (mmol/l)

31 Event SHARP: Major Atherosclerotic Events Eze/simv Placebo Risk ratio & 95% CI (n=4650) (n=4620) Major coronary event 213 (4.6%) 230 (5.0%) Non-hemorrhagic stroke 131 (2.8%) 174 (3.8%) Any revascularization 284 (6.1%) 352 (7.6%) Major atherosclerotic event 526 (11.3%) 619 (13.4%) 16.5% SE 5.4 reduction (p=0.0022) Other cardiac death 162 (3.5%) 182 (3.9%) Hemorrhagic stroke 45 (1.0%) 37 (0.8%) Other major vascular events 207 (4.5%) 218 (4.7%) 5.4% SE 9.4 reduction (p=0.57) Major vascular event 701 (15.1%) 814 (17.6%) 15.3% SE 4.7 reduction (p=0.0012) Eze/simv better Placebo better

32 The Need to Study HDL Function: Potential Novel Therapeutic Approaches. LCAT modulation LxR agonists FxR agonists BAR agonists PPARα agonists Apo AI Prod RVX208 LxR agonists Dalcetrapib Anacetrapib PPARα agonists (Fibrates) Figure 1

33 Fibrates

34 On-Going Studies : Niacin AIM-HIGH: Niacin Plus Statin to Prevent Vascular Events Age: >45 years, CAD + Dyslipidemia Simvastatin 40mg daily Randomized to: Niacin 2 g/day n=3, Sponsor: NHLBI

35 On-Going Studies : Niacin HPS-2 THRIVE: Treatment of HDL to Reduce the Incidence of Vascular Events HPS2-THRIVE Age: years, CAD, PVD, DM Simvastatin 40mg daily +/- ezetimibe 10mg Randomized to: Niacin/Laropriprant 2 g/day n=25, Sponsor: Merck

36 On-Going Studies: Dalcetrapib DAL-Outcomes: A Randomized, Double-blind, Placebocontrolled Study Assessing the Effect of RO on Cardiovascular Mortality and Morbidity in Clinically Stable Patients With a Recent Acute Coronary Syndrome Age: >45 years, ACS Optimal medical treatment Randomized to: RO (Dalcetrapib)600mg po daily n=15, Sponsor: Hoffmann-La Roche

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38 LDL-C (mg/dl) (SE) HDL-C (mg/dl) (SE) Anacetrapib: Effects on LDL-C and HDL-C 100 LDL-C 120 HDL-C % (p<0.001) % (p<0.001) Anacetrapib Placebo 20 Anacetrapib Placebo 0 Baseline Wk 6 Wk 12 Wk 18 Wk 24 Wk 30 Wk 46 Wk 62 Wk 76 0 Baseline Wk 6 Wk 12 Wk 18 Wk 24 Wk 30 Wk 46 Wk 62 Wk 76 Anacetrapib n = Placebo n = Study Week Anacetrapib n = Placebo n = Study Week

39 Conclusions Modulation of HDL function for the prevention and treatment of CVD shows great promise Biomarkers of HDL function (and not solely HDL-C mass) are required in pre- and early clinical trials Eventually, outcome-driven clinical trials will be absolutely required

40 Conclusions LDL-C lowering is well established The method of LDL-C lowering (diet, statins, BAR, Ezetimibe) appear irrelevant HDL modulating drugs are the next frontier in preventive cardiology.

41 Vascular Inflammation

42 Questions Are inflammatory diseases a risk factor for CVD? Do markers of inflammation predict risk? Should this influence screening and treatment? What is new in inflammation and CVD?

43 Atherosclerosis

44 Inflammation and Atherosclerosis

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46 Inflammatory Diseases and CVD Can J Cardiol 2011;27:

47 Inflammatory Diseases and CVD MI CVD CVD deaths Lupus Erythomatosus Rheumatoid Arthritis Ankylosing Spondylitis Psoriatic Arthritis Polymyositis / Dermatomyositis Inflammatory Bowel Disease Roifman I et al. Can J Cardiol 2011;27:

48 CRP: A biomarker of atherosclerosis or a causal factor?

49 Meta-analysis of 54 Prospective Cohort Studies: The magnitude of independent risk associated with hscrp is at least as large, if not larger, than that of BP and cholesterol However, no randomized trials of inflammation reduction have been carried out to date Risk Ratio (95%CI) hscrp Systolic BP Total cholesterol Non-HDLC 1.37 ( ) 1.35 ( ) 1.16 ( ) 1.28 ( ) Risk Ratio (95%CI) per 1-SD higher usual values Emerging Risk Factor Collaborators, Lancet January 2010

50 Proof of Concept Is a strategy based on hscrp risk determination and treatment effective? The JUPITER Study

51 JUPITER Trial Design JUPITER Multi-National Randomized Double Blind Placebo Controlled Trial of Rosuvastatin in the Prevention of Cardiovascular Events Among Individuals With Low LDL and Elevated hscrp No Prior CVD or DM Men >50, Women >60 LDL <130 mg/dl hscrp >2 mg/l 4-week run-in Rosuvastatin 20 mg (N=8901) Placebo (N=8901) MI Stroke Unstable Angina CVD Death CABG/PTCA Argentina, Belgium, Brazil, Bulgaria, Canada, Chile, Colombia, Costa Rica, Denmark, El Salvador, Estonia, Germany, Israel, Mexico, Netherlands, Norway, Panama, Poland, Romania, Russia, South Africa, Switzerland, United Kingdom, Uruguay, United States, Venezuela Ridker et al, Circulation 2003;108:

52 LDL (mg/dl) JUPITER Achieved LDLC, Achieved hscrp, or Both? hscrp (mg/l) LDL decrease 50 percent at 12 months Is the large benefit observed in the JUPITER trial due to lipid lowering, to inflammation inhibition, or to a combination of these two processes? hscrp decrease 37 percent at 12 months Months

53 JUPITER Primary Trial Endpoint : MI, Stroke, UA/Revascularization, CV Death Cumulative Incidence Ridker et al NEJM 2008 HR 0.56, 95% CI P < Number Needed to Treat (NNT 5 ) = Placebo 251 / % Rosuvastatin 142 / 8901 Number at Risk Rosuvastatin Placebo Follow-up (years) 8,901 8,631 8,412 6,540 3,893 1,958 1, ,901 8,621 8,353 6,508 3,872 1,963 1,

54 JUPITER LDL reduction, hscrp reduction, or both? Ridker et al Lancet 2009;373: N Rate Placebo LDL>70mg/dL,hsCRP>2 mg/l LDL<70mg/dL,hsCRP>2 mg/l LDL>70mg/dL,hsCRP<2 mg/l LDL<70mg/dL,hsCRP<2 mg/l P < Placebo LDL>70mg/dL,hsCRP>1 mg/l LDL<70mg/dL,hsCRP>1 mg/l LDL>70mg/dL,hsCRP<1 mg/l LDL<70mg/dL,hsCRP<1 mg/l Full Adjusted Hazard Ratio 0.21, 95% CI , P < Rosuvastatin Better P < Rosuvastatin Worse

55 Conclusion from JUPITER A screening strategy that includes hscrp influences therapeutic decisions and alters outcomes favorably. Few physicians are buying it

56 Biomarkers and Cardiovascular Risk: Update 2011 Circulation. 2010;122:e JACC 2010;50:

57 BIOMARKERS: Serum/Plasma Apolipoproteins* Atrial Natriuretic Peptide (ANP) hscrp HgA1c Lipoprotein-associated phospholipase A2 Inflammatory biomarkers (spla2, IL) Homocysteine Class III Class III Class IIa Class IIb Class IIb N/A N/A * Apo AI, apo B, LDL particle size by gel or NMR, HDL particle size, density JUPITER indications (Same as in Canada)

58 Is CRP Causal in Atherosclerosis? Epidemiological association does not imply causality Animal data Mendelian Randomization

59 Animal Models Torzewski M, et al. No effect of C-reactive protein on early atherosclerosis in LDLR -/- / human C-reactive protein transgenic mice. Thromb Haemost. 2008;99:196 Ortiz MA, et al. Continuously-infused human C-reactive protein is neither proatherosclerotic nor proinflammatory in apolipoprotein E-deficient mice. Exp Biol Med 2009;234:624 Tennent GA, et al. Transgenic human CRP is not pro-atherogenic, pro-atherothrombotic or pro-inflammatory in apoe -/- mice. Atherosclerosis ;196:248 Trion A, et al. No effect of C-reactive protein on early atherosclerosis development in apolipoprotein E*3-Leiden/human C-reactive protein transgenic mice. ATVB. 2005;25:1635 Hirschfield GM, et al. Transgenic human C-reactive protein is not proatherogenic in apolipoprotein E-deficient mice. PNAS 2005 ;102:8309

60 Mendelian Randomization Implies causality of a gene product (intermediary phenotype) in a disease process Gene IP Often used, perhaps wrongfully, to dismiss a gene or its product as a causal factor

61 Genetic Determinants of Plasma CRP Level Dehgman et al, Circulation 2011;123:731-8

62 Mendelian Randomization CRP Genetics and Outcome Zacko et al NEJM 2008;359:1897.

63 Conclusion: Human genetic data indicate that C reactive protein concentration itself is unlikely to be even a modest causal factor in coronary heart disease. Authors, Engert J et al. BMJ Feb 15;342:d548. doi: /bmj.d548.

64 The forest plots show the meta-analysis of the association of the CRP genetic risk score with MI (A) and CHD (B). Dehghan A et al. Circulation 2011;123: Copyright American Heart Association

65 Take Home Point Based on animal models and Mendelian randomization experiments, it is unlikely that CRP plays a causal role in atherosclerosis hscrp is a non-specific biomarker of inflammation

66 Gout: Uric acid crystalopathy

67 Questions / Objectives What is Cryopyrin-Associated Periodic Syndrome (CAPS)? Are cholesterol crystals only seen in latestage atherosclerosis? What is the inflammasome? Is this useful clinically?

68 Answers CAPS is a spectrum of autoinflammatory syndromes including; Familial cold autoinflammatory syndrome (FCAS, formerly termed familial cold-induced urticaria) Muckle-Wells syndrome (MWS), and Neonatal-onset multisystem inflammatory disease (NOMID, also called chronic infantile neurologic cutaneous and articular syndrome or CINCA) No: Cholesterol crystals may initiate atherosclerosis through: NLRP3 complex: the inflammasome Does this matter? We ll see with CANTOS

69 Cholesterol Crystals in Plaques

70 Cholesterol Crystals Absent in Normal Arteries

71 Cholesterol Crystals in Early Plaques

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73 Cholesterol Crystals Can Lead to Inflammation of Arteries Abela G, et al. NLRP3 inflammasomes are required for atherogenesis and activated by cholesterol crystals. Nature 2011;464,

74 Duewell, P, et al, Nature 2010; 464: Rajamaki K et al, PLoS One 2010;5:e11765

75 Proposed mechanism of cholesterol crystal (CHC)-induced inflammasome activation Rajamäki K. PLoS One. 2010; 5(7): e11765

76 Mononuclear Phagocytes IL-1 IL-6 Libby P. Inflammation and atherosclerosis. Nature 2002;420:868 Arnaud C et al. Statins reduce IL6 induced CRP secretion in human hepatocytes ATVB 2005;25;1231 CRP

77 Cholesterol crystals activate the caspase-1-activating NLRP3 inflammasome to generate IL-1b and initiate atherosclerosis Endogenous Danger Signal Innate immune cell Phagolysosome IL-1b IL-1b Cholesterol Crystals; Modified LDL Lysosome NLRP3 Inflammasome Cathepsin B ASC NLRP3 Cardinal Pro-caspase-1 Phagosome IL-1b Caspase-1 Pro-IL-1b Vascular inflammation hscrp IL-6 IL-1b Duewell et al, Nature (2010) 464: Rajamaki K et al, PLoS One 2010;5:e11765 Liver IL-1B mab or IL-1rA

78 The Inflammasome Inflammasomes are large, multimeric protein complexes that link the sensing of microbial products and metabolic stress to the proteolytic processing of prointerleukin (pro-il)-1β to its active form. NATURE CLINICAL PRACTICE RHEUMATOLOGY 2008 VOL 4 NO 1

79 NATURE CLINICAL PRACTICE RHEUMATOLOGY 2008 VOL 4 NO 1

80 The Inflammasome The inflammasome is a multiprotein oligomer and is a component of the innate immune system. The inflammasome promotes the maturation of inflammatory cytokines interleukin 1-β and interleukin 18. The inflammasome is responsible for activation of inflammator processes, and has been shown to induce cell pyroptosis, a process of programmed cell death distinct from apoptosis.

81 Points to Take Home Vascular Inflammation is triggered by many stimuli including cholesterol crystals Mononuclear cells accumulate at sites of inflammation Mediators of inflammation propagate the inflammatory response Biomarkers of inflammation increase in serum

82 The Balance of IL-1 and IL-1Ra : Contribution to Human Disease Pro-Inflammatory Anti-Inflammatory NLRP3 cryopyrin Inflammasome IL-1R Severe Imbalance (Inflammasome mutations) CAPS, MWS, NOMID

83

84 The Balance of IL-1 and IL-1Ra : Contribution to Human Disease Pro-Inflammatory Anti-Inflammatory NLRP3 cryopyrin Inflammasome IL-1R Severe Imbalance Moderate Imbalance Mild Imbalance (Inflammasome mutations) CAPS, MWS, NOMID Psoriasis, contact hypersensitivity syndromes Gout, inflammatory arthritis, Crohn s, Ulcerative colitis Autoimmune Disorders, thyroiditis Atherosclerosis, Diabetes

85 IL-1: Potential Roles in Atherogenesis and Methods of Inhibition IL-1 type II Decoy Receptor IL-1r/IL-1r accessory protein IL-1 trap inos Endothelin-1 IL-1a,b IL-1 type 1 Receptor Chemokines/cytokines Adhesion molecules Anti IL-1b antibody Canakinumab IL-1 Receptor Antagonist Endogenous Exogenous Endothelial & Smooth Muscle Proliferation Macrophage Activation Endothelial Dysfunction Athero-progression Adapted from Fearon W, Fearon D. Circulation 2008;117:2577-9

86 Targeted Inactivation of IL-1b Kirii et al. (2003) Arterioscler Thromb Vasc Biol 23:656 Decreased atherosclerosis in mouse model of atherosclerosis (apo E -/- /IL-b -/- fed a high cholesterol diet.

87 Lack of IL-1b decreases severity of atherosclerosis in ApoE-deficient mice ApoE KO ApoE KO, IL-1b KO Kirii et al. (2003) Arterioscler Thromb Vasc Biol 23:656

88 Application of IL-1b promotes arterial intimal thickening in porcine coronary artery Shimokawa et al. (1996) J Clin Invest 97:769

89 Genetic Determinants of Plasma CRP Level Dehgman et al, Circulation 2011;123:731-8

90 Targeted Inactivation of IL-1b In Man The CANTOS Study

91 Canakinumab Anti-inflammatory Thrombosis Outcomes Study (CANTOS) To directly test the inflammatory hypothesis of atherothrombosis To determine whether long-term inhibition of interleukin-1b with canakinumab (50 mg,150 mg or 300 mg SQ every three months) as compared to placebo will reduce rates of recurrent cardiovascular events among stable post-myocardial infarction patients who remain at elevated vascular risk due to increased levels of hscrp (> 2 mg/l) despite usual care, including statin therapy. 91

92 What about secondary prevention? Clinical Relevance of Achieved hscrp in Stable ACS Patients After Treatment with Statin Therapy Cumulative Rate of Recurrent Myocardial Infarction or Coronary Death (percent) hscrp>2 mg/l hscrp<2 mg/l Ridker et al NEJM 2005;352: Follow-Up (years)

93 Immunomodulation by Inhibition of Cytokines TNF-a: IL-1b IL-1R Il-6 adalinumab (HUMIRA); infliximab (REMICADE); ethenercept (EMBREL) canakinumab (ILARIS) anakinra (KINERET) mimics IL-1RA tocilizumab (ACTEMRA) (elsilimumab in cancers)

94 Canakinumab high-affinity human monoclonal anti-human interleukin-1b (IL-1b) antibody currently indicated for the treatment of IL-1b driven inflammatory diseases (Cryopyrin-Associated Period Syndrome [CAPS], Muckle-Wells Syndrome) designed to bind to human IL-1b and functionally neutralize the bioactivity of this pro-inflammatory cytokine long half-life (4-8 weeks) with CRP and IL-6 reduction for up to 3 months

95 Issues in the Selection of Anti-inflammatory Agents for Trials of Cardiovascular Inflammation Inhibition Statins TNF inhibition IL-6 Inhibition IL-1b inhibition TC LDL HDL TG Chylo CRP / IL-6

96 Potential Strengths of IL-1b Antagonism in Atherothrombosis Selective: an important pro-inflammatory mediator, but not essential for host defense Leaves IL-1a signaling intact Implicated in atherothrombosis and plaque rupture in several preclinical and clinical studies Potentially beneficial effects without altering lipids or platelet function Safety, tolerability, and adverse effect profiles acceptable for a secondary prevention trial

97 Conclusions The relationship between cholesterol and inflammation and atherosclerosis is better understood Cholesterol crystals activate the inflammasome In turn, IL-1b (and IL-18) are secreted by macrophages, initiating a local systemic reaction A low-grade systemic inflammation is also initiated by other cytokines (IL-6); this can be measured by biomarkers such as hscrp

98 Final Conclusions We still have a lot to learn